Although the cell biology of haemopoietic stem cells (HSC) is relatively well understood, their molecular control is less well defined. Due to the rarity of this cell type, their incompletely defined phenotype and difficulty in generating null alleles by somatic transgenesis of HSC, alternative approaches to their study have been sought. Embryonal stem (ES) cells are toti-potential, can transmit transgenes through the germ line and have recently been shown to produce HSC in vitro. This chapter reviews the utility of gene knock-outs in ES cells in the study of molecular haemopoiesis, indicates how ES cells can be used in vitro as a strategy both for the identification of genes controlling early haemopoietic events and the analysis of their function, and outlines how emerging techniques that exploit the biology of ES cells might prove to be powerful tools in the genetic dissection of the mechanisms controlling haemopoiesis.